3-(2,2,2-Trimethylhydrazinium) propionate is disclosed in U.S. Pat. No. 4,481,218.
It is well known that 3-(2,2,2-trimethylhydrazinium) propionate as dihydrate (this substance being known under its International Nonproprietary Name of Meldonium) is widely used for controlling carnitine and gamma-butyrobetaine concentration ratio and consequently the speed of fatty acid beta-oxidation in the body (Dambrova M., Liepinsh E., Kalvinsh I. Mildronate: cardioprotective action through carnitine-lowering effect. Review.//Trends Cardiovasc. Med.-2002.-Vol. 12, N.6. -P. 275–279. Rupp H., Zarain-Herzberg A., Maisch B. The use of partial fatty acid oxidation inhibitors for metabolic therapy of angina pectoris and heart failure//Herz, 2002-Vol. 27, N.7.-P. 621–636. Mildronate, Met-88. Drugs Fut. 2001, 26(1), p. 82).
Due to these properties, Meldonium (registered with the trade mark of “MILDRONĀTS®”, “MILDRONATE®”, “MPOHAT®”) is extensively applied in medicine as an anti-ischemic un stress-protective drug in treating various cardio-vascular diseases and other pathologies involving tissue ischemia (R. S. Karpov, O. A. Koshelskaya, A. V. Vrublevsky, A. A. Sokolov, A. T. Teplyakov, I. Skarda, V. Dzerve, D. Klintsare; A. Vitols, I. Kalvinsh, L. Matveyeva, D. Urbane. Clinical efficacy and safety of Mildronate in patients with ischemic heart disease and chronic heart failure. Kardiologiya, 2000, Vol. 6, -P. 69–74.)
However, Meldonium as dihydrate has essential drawbacks, the first of which consists in its rather high hygroscopicity. Already after 24 hours maintenance at 100% air humidity, Meldonium mass is increased by 10% because of water absorption, the substance being transformed into a syrup.
Other essential drawback of Meldonium is caused by the half-elimination period equalling 4–10 hours for humans while this drug must be used 2–4 times daily in the clinic (V. Dzērve. Mildronāts. PAS “Grindeks”, 1999, p. 1), though it is longer in trials on rats (K. Yoshisue, Y. Yamomoto, K. Yoshida, M. Saeki, Y. Minami, Y. Esumi, Y. Kawaguchi. Pharmacokinetics and biological fate of 3-(2,2,2-trimethylhydrazinium)propionate (MET-88), a novel cardioprotective agent, in rats. Drug Metabolism and Disposition, vol. 28, No 6, 687–694).
As Meldonium dihydrate is unsuitable for single daily oral introduction, it was one of the aims of the present invention to find other pharmacologically acceptable Meldonium forms which would be applicable for single daily use. It is generally known that amino acid betaine salts usually have good solubility in water. If pharmacologically acceptable acids are selected, resorption and elimination pharmacokinetics and biological activity of these salts normally does not much differ from the parameters of the initial compound.
Besides, Meldonium is not very stable: while heated, it fast loses the water of the crystal hydrate. In turn, the anhydrous form of Meldonium is unstable and extremely hygroscopic. In such form, this compound soon becomes coloured and gets a specific annoying odour. Thus, the hygroscopicity and thermal non-stability of Meldonium dihydrate are significant disadvantages restricting the possibilities of preparing different oral and external drug dosage forms from this compound. Furthermore, Meldonium dihydrate is actively dehydrated at temperatures so low as 40–45° C. This means that sure storage of Meldonium dosage forms containing crystal hydrate is rather embarrassing in countries with hot climate.
Because Meldonium dihydrate is not readily applicable for producing drug oral dosage forms, it was a further object of this invention to find other pharmacologically acceptable salts of Meldonium which would lack hygroscopicity or/and, be thermally stable and could be stored in any climatic zone for a long time.